tbuckley/cabot-search huggingface dataset:
A multicenter, randomized, double-blind, phase III trial comparing denosumab biosimilar QL1206 and denosumab in patients with bone metastases from solid tumors.
Authors: Huiping Li, Yan Huang, Li Zhang, Zhendong Chen, Aiping Zeng, Helong Zhang, Yan Yu, Shihong Wei, Qingshan Li, Xiaojia Wang, Xiangcai Wang, Xiuwen Wang, Runxiang Yang, Xiumei Dai, Minghong Bi, Tao Sun, Qingyuan Zhang, Cuicui Han, Qianqian Liu, Yujie Li
Journal: Journal of Clinical Oncology (2022)

2526 Background: This phase III study compared clinical efficacy, safety of the first biosimilar QL1206 with denosumab in solid tumor patients with bone metastases. Methods: Patients aged 18-80 years, with bone metastatic solid tumors and ECOG performance status of 0-2 were randomly assigned 1:1 to receive subcutaneous QL1206 or denosumab (120 mg Q4W, both) based on stratification factors (tumor types, previous skeletal-related event [SRE], and current systemic anti-tumor therapy). The primary efficacy endpoint was the percentage changes from baseline to week 13 in urinary N-telopeptide/creatinine ratio (uNTX/uCr); Clinical equivalence would be confirmed if the two-sided 90% confidence intervals (CI) of the least-squares mean (LSM) difference of natural log-transformed ratio of week 13 uNTX/uCr to baseline calculated by analysis of covariance were within the margins of ±0.135. The secondary endpoints included the percentage changes from baseline to week 25 and 53 in uNTX/uCr, the percentage changes from baseline to week 13, 25 and 53 in serum bone-specific alkaline phosphatase (s-BALP) and the time to on-study SRE. Adverse events (AE), immunogenicity (IG) and pharmacokinetics (PK) were also assessed. Population PK was analyzed using nonlinear mixed effects model. Results: 717 patients were randomized to the QL1206 (n = 357) and denosumab (n = 360) groups, respectively. The median percentage changes at week 13 in uNTX/uCr were -75.2% for QL1206 and -75.8% for denosumab. LSM of natural log-transformed ratio of week 13 uNTX/uCr to baseline were -1.429 (standard error 0.130) and -1.441 (0.130) in the two groups. The LSM difference between the two groups was 0.012 (90% CI -0.078 to 0.103; P = 0.8208), within the equivalence margins. Analyses for subgroups of sex, age, and randomization strata showed almost no significant differences. The secondary endpoints were also similar between the two groups (median percentage changes in s-BALP from baseline to week 13: -38.0% vs -37.1%; hazard ratio of time to SRE: 1.264 [95% CI 0.670 to 2.383]; both P &gt; 0.05). In the safety set, treatment-emergent AE occurred in 332 of 356 patients (93.3%) in the QL1206 group and 348 of 361 (96.4%) in the denosumab group. The proportions of positive anti-drug antibody (14/345 [4.1%] vs 16/352 [4.5%]), neutralizing antibody (three [0.9%], each), and PK characteristics were similar between the two groups. Conclusions: The results suggest that QL1206, the first biosimilar denosumab, is similar to denosumab with respect to clinical efficacy, acceptable safety, IG, and PK characteristics. The totality of evidence supports clinical equivalence of QL1206 and denosumab. Clinical trial information: NCT04550949.
IMG-16. Non-invasive metabolic imaging of response to therapy in diffuse midline gliomas
Authors: Georgios Batsios, Celine Taglang, Meryssa Tran, Anne Marie Gillespie, Javad Nazarian, Sabine Mueller, Pavithra Viswanath
Journal: Neuro-Oncology (2022)

Abstract Diffuse midline gliomas (DMGs) are universally lethal pediatric tumors that are defined by the presence of histone H3K27 alterations. The infiltrative nature and anatomical location of these tumors prohibit surgical resection. Radiotherapy, which is standard of care, does not significantly enhance long-term outcome. Novel therapies are sorely needed for DMG patients. Imipridone drugs ONC201 and ONC206 have demonstrated anti-tumor activity in preclinical cancer models, including DMGs and have shown promise in pilot studies in DMG patients. Successful clinical deployment of imipridones requires the identification of companion imaging biomarkers that report on response to therapy. Magnetic resonance spectroscopy (MRS) is a safe, non-radioactive, non-invasive method of imaging metabolism in vivo. 1H-MRS assesses steady-state metabolite levels and is used in clinics. 2H-MRS following administration of 2H-labeled substrates is a novel, clinically translatable method of imaging metabolic pathway activity. Our results indicate that treatment of SF7761 DMG cells with ONC206 causes a significant reduction in 1H-MRS-detectable lactate, glutamate, glutathione and phosphocholine, pointing to inhibition of glycolysis, oxidative phosphorylation, redox and phosphatidylcholine biosynthesis respectively. Examination of [6,6’-2H]-glucose metabolism using 2H-MRS indicates that lactate production from [6,6’-2H]-glucose is significantly reduced in ONC206-treated SF7761 cells relative to controls. We then investigated the effect of ONC206 on mice bearing orthotopic SF8628 DMG tumors. At day 7 following the treatment onset, at a timepoint when no change in tumor volume can be observed by anatomical imaging, in vivo1H-MRS-detectable lactate and total choline are reduced relative to day 0. Collectively, our studies indicate that imipridones induce alterations in DMG metabolism that can be leveraged for non-invasive 1H- and 2H-MRS-based imaging of response to therapy. By providing clinicians with an early readout of treatment response prior to anatomical changes, our biomarkers will enable early assessment of treatment response and, thereby, clinical translation of these promising therapeutics.
Optimizing a team approach for successful accrual to and conduct of clinical trials in a community oncology practice.
Authors: Christa M Braun-Inglis, Janela Agonoy, Jami Aya Fukui
Journal: Journal of Clinical Oncology (2022)

e13524 Background: Oncologists and advanced practice providers (APPs) routinely work as part of a team to provide quality cancer care in today’s healthcare environment. However, this does not always translate into the realm of clinical research. It is estimated that only 2-8% of the adult oncology population enrolls in a clinical trial, with more than 20% of current trials failing to meet accrual goals. These numbers are projected to be even worse due to the impact of the COVID pandemic. Our Oncologist/APP team in conjunction with a clinical research coordinator (CRC) set out to develop a workflow to approach and offer clinical trials to patients in our practice with the goal of increasing clinical trial accrual and improving clinical trial conduct. Methods: Between 1/1/19-12/31/21, a community breast oncology focused practice in the Hawaii M/U NCORP implemented a plan with the goal to increase accrual to clinical trials. Building on the prior experience of both clinicians, the practice developed a comprehensive team approach between the Oncologist, APP, and CRC. This approach included four components: 1) Clinic workflow for clinical trial screening, introduction, and follow-up of potential participants; 2) Shared clinical trial visits between MD &amp; APP; 3) Protocol reviews by MD who reviewed treatment protocols &amp; APP who reviewed symptom management and cancer care delivery research (CCDR) protocols. All clinical trial reviews were discussed with CRC for coordination input; 4) Protocol leadership between MD serving as local primary investigator (PI) on treatment trials, APP serving as local PI and/or site champion on symptom management and CCDR protocols. Results: From 2019-2021, our practice was able to accrue over 23% of our patients to clinical trials in a community practice setting, despite the COVID-19 Pandemic. Of the 149 unique accruals during this period, 59% of accruals were interventional trials and 41% were observational trials. Clinical trial accrual was racially diverse and mirrored the patient population. During this period, there were minimal protocol deviations observed based on review of shadow charts on this group of clinical trial patients. Conclusions: Through this team approach, our practice has been successful in having a high rate of clinical trial accrual while maintaining excellent clinical trial conduct even during the pandemic. We believe our team approach that utilizes the APP to the full scope of practice along with CRC empowerment in addition to the engaged oncologist is key to our success. Oncology practices and healthcare systems must value and engage all potential members of the team to maximize their clinical trial ability and to continue to offer/enroll patients in clinical trials as the standard of care.
Beneficial effects of exercise training on expression of fibrosis-related genes in a mouse model of hypertrophic cardiomyopathy
Authors: K Andreassen, C Rixon, IM Hauge-Iversen, I Sjaastad, G Christensen, T Edvardsen, KH Haugaa, IG Lunde, MK Stokke
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): South-Eastern Norway Regional Health Authority (HSØ) KG Jebsen Cardiac Research Center Background The effects of exercise training prior to manifestation of phenotype in hypertrophic cardiomyopathy (HCM) are unknown. In mice carrying the HCM-pathogenic α-MHC R403Q/+ (R403Q) genetic variant, accelerated progression of the HCM phenotype is induced by cyclosporine A (CsA). We used this model to determine if exercise training initiated before phenotype development could limit disease severity. Methods R403Q mice were allocated to treadmill exercise training (N=23) or sedentary behavior (N=23) for 6 weeks. For the last three weeks of the 6-week period, all mice received CsA to induce the HCM phenotype. Cardiac imaging (echocardiography or MRI) and exercise testing were performed at the 0, 3 and 6-week time points. After the 6-week exercise protocol, left ventricles were harvested for molecular analyses. Results After 6 weeks, exercise trained mice ran 2-fold further during testing than sedentary mice (p&amp;lt;0.0001), and 2-fold further than at baseline (p&amp;lt;0.0001). There was no difference in VO2 max between groups. Cardiac imaging did not reveal differences in hypertrophy between exercised and sedentary HCM mice. However, we observed a reduction in cardiac expression of key fibrosis-related genes in the exercise group, i.e. Col1a2 to 49 % (p=0.03), Col1a1 to 50 % (p=0.03), Col3a1 to 46 % (p=0.02), Fn1 to 49 % (p=0.01) and Lox to 58 % (p=0.05) of levels in the sedentary group. HPLC did not reveal differences in collagen protein. Conclusion Exercise training initiated prior to manifestation of the HCM phenotype in mice results in lowered production of key fibrosis-related genes, including structural collagens. Further analysis is needed to determine the functional consequences of these beneficial changes in gene expression.
Amivantamab Emerges Positively from Its “Chrysalis”
Journal: Cancer Discovery (2022)

The phase I CHRYSALIS trial found that patients with non-small cell lung cancer who carry a MET exon 14 skipping mutation responded well to treatment with amivantamab. The overall response rate (ORR) to the bispecific antibody was 33%, and median progression-free survival was 6.7 months. Amivantamab also showed encouraging efficacy in the phase I/Ib CHRYSALIS-2 study, which tested the agent in combination with lazertinib. Among patients whose disease advanced despite treatment with osimertinib, the ORR was 33% and the median overall survival was 14.8 months.
Estradiol (E2) levels in premenopausal women with hormone receptor-positive (HR+) breast cancer (BC) on ovarian function suppression (OFS) with gonadotropin-releasing hormone agonists (GnRHa).
Authors: Megan Elizabeth Tesch, Yue Zheng, Shoshana M. Rosenberg, Philip Daniel Poorvu, Kathryn Jean Ruddy, Rulla Tamimi, Lidia Schapira, Jeffrey M. Peppercorn, Virginia F. Borges, Steven E. Come, Craig Snow, Ann H. Partridge
Journal: Journal of Clinical Oncology (2022)

524 Background: OFS is an important treatment component for premenopausal women with early and advanced HR+ BC and optimal efficacy may depend on complete E2 suppression with GnRHa, especially when combined with aromatase inhibitors (AI). However, standard assays lack sensitivity and accuracy at very low E2 concentrations, rendering detection of breakthrough ovarian function challenging. More informative data regarding endocrine effects of GnRHa are needed, particularly in young women who derive the most benefit from OFS yet more frequently had breakthrough E2 levels in the SOFT trial substudy, SOFT-EST. Methods: Using a prospective cohort study of women with BC diagnosed at age ≤ 40 years, we identified participants with stage I-IV HR+ BC on OFS treatment with leuprolide, goserelin or triptorelin and blood collected 1 year after diagnosis. Clinical data were obtained through surveys and medical records. Plasma estrogens were measured by liquid chromatography-tandem mass spectrometry, with a limit of detection of 0.2 pg/mL compared to 10 pg/mL with standard assays. We assessed the proportion of women on OFS with E2 &gt; 2.72 pg/mL (10 pmol/L) and &gt; 10 pg/mL. Patient characteristics, estrone (E1) and FSH levels, and disease-free (DFS) and overall survival (OS) were compared between those with and without elevated E2 using Fischer’s exact, Wilcoxon rank sum and log rank tests, respectively. Results: Of 84 patients who met inclusion criteria, 72 (86%) had stage I-III and 12 (14%) had stage IV BC; 25 were on OFS plus AI and 59 were on OFS plus tamoxifen (TAM). Median E2 was 3.1 pg/mL (range 0.2-30.9). 46 patients (55%) had E2 &gt; 2.72 pg/mL, including 8 on AI and 38 on TAM; 4 (5%) had E2 &gt; 10 pg/mL, including 1 on AI and 3 on TAM. Factors associated with E2 &gt; 2.72 pg/mL were no prior chemotherapy, TAM and high E1 ( P ≤.05), but not age, BMI or GnRHa schedule (Table). After a median follow-up of 7 years, DFS events were seen in 6 patients with E2 &gt; 2.72 pg/mL and 5 without ( P =.232); OS events were seen in 7 patients with E2 &gt; 2.72 pg/mL and 5 without ( P =.608). Conclusions: More than half of young women with ER+ BC had E2 &gt; 2.72 pg/mL on OFS, 91% of whom would not have been detected by standard assays. This may be an area amenable to intervention to improve outcomes in young women. However, larger studies are needed to elucidate the optimal E2 target on OFS and clinical implications of incomplete E2 suppression on ultrasensitive assays. [Table: see text]
RONC-14. Olfactory Perception During Proton Radiation and Differences in Frequency of Olfactory Perceptions Based on Proton Craniospinal Irradiation Technique for Pediatric Brain Tumor Patients.
Authors: Myrsini Ioakeim-Ioannidou, Parsa Erfani, Tobias Urell, Juliane Daartz, Julia Berv, Shannon Leahy, Barbara Fullerton, Rachel Bolton, Torunn Yock, Nancy Tarbell, Beow Yeap, Shannon MacDonald
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Unusual olfactory perception has been reported during brain radiation treatments but is infrequent and does not typically interfere with the ability to deliver treatment or cause notable distress. Methods: We performed a retrospective review of 127 pediatric patients treated with proton radiation therapy (PRT) for primary brain tumors in a single institution between 2016-2021. Patients received PRT to the brain as part of craniospinal irradiation (CSI) followed by a boost to the brain. Proton CSI was delivered with 3D-CRT protons (n=53) or pencil beam scanning technique (PBS) (n=74). Within the PBS group, treatment delivery to the CSI utilized a single PA field (n=24) or two posterior oblique fields (n=50). We collected data on abnormal olfactory sensations, nausea/vomiting, and the use of medical intervention for those symptoms. Results: Our cohort included 80 males and 47 females. The median age of patients was 10 years old (range, 3 – 21). Seventy-one patients received concurrent chemotherapy. Prior to PRT, 31 patients were nauseous. During the radiation course, 104 patients developed worsening nausea while 63 patients reported emesis. Four patients vomited while receiving radiation. Seventeen patients reported olfactory perceptions during CSI. We found a higher rate of olfactory perception in patients treated with PBS (n=16, 22%) than 3D-CRT (n=1, 2%) (p=0.001) and, within the PBS group, patients treated with a single PA field (n=11, 46%) than two oblique fields (n=5, 10%) (p=0.002). Seventy-eight patients required intervention including addition of anti-emetic or anti-anxiety medication. Two patients required sedation due to the malodorous smell during CSI. We did not find any significant difference in nausea/vomiting based on treatment technique. Conclusions: PBS and PBS technique influence olfactory perceptions but not the occurrence of the rate of nausea/vomiting. Further studies should be performed to validate these findings and determine techniques to minimize unpleasant olfactory perceptions.
MEDB-39. Oncogenic mechanisms underlying GLI2-amplified medulloblastoma
Authors: Najiba Murad, Jiao Zhang, Xiao Liu, Ran Tao, Michael Taylor, Yanxin Pei
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children. There are several subtypes of MB, and among them, the subtype of GLI2-amplified SHH-MB associated with P53 mutations has the worst prognosis and a poor survival rate; the 5-year survival rate is &amp;lt;30%. Moreover, the GLI2-amplified MBs are non-responsive to the only targeted treatment option available for SHH-MB, the SMO inhibitors. This leaves an unmet critical treatment gap, and there is an urgent need to identify novel targets to develop effective therapeutics. However, a deeper understanding of the cellular and molecular mechanisms driving GLI2-amplified MB tumorigenesis is currently lacking. With a focused goal to resolve this particular type of MB tumorigenesis, we recently generated an engineered mouse model of GLI2-driven MB. Using this model, we demonstrated that GLI2 is the critical driver of tumorigenesis and identified granule cell progenitors (GCPs) as the cells of origin. Interestingly, we have also found that GLI2 drives only Math1+ embryonic GCPs but not neonatal GCPs to form SHH-MB. Correspondingly, our scRNA-seq analysis revealed that the MAPK pathway is specifically enriched in embryonic but not neonatal Math1+ GCPs. Moreover, the MAPK pathway is activated in mouse and human GLI2-driven MB tumors, and a MEK/ERK inhibitor significantly delayed the growth of GLI2-driven MB in vivo. Based on these exciting results, we hypothesize that GLI2-driven MB originates from a specific cell population of Math1+ GCPs and in a particular spatiotemporal window during cerebellar development, and targeting MAPK/MEK/ERK pathway may represent a novel effective approach to treating GLI2-amplified MB.
Error in Author Affiliations
Journal: JAMA Network Open (2022)

Dedeepya Konuthula, MD; Flor de Abril Cameron, MPH; Naudia Jonassaint, MD, MHS; Eloho Ufomata, MD; Orquidia Torres, MD, MS; Utibe R. Essien, MD, MPH; Megan E. Hamm, PhD; Jessica Merlin, MD, PhD; Maya I. Ragavan, MD, MPH, MS
Retrospective single system analysis of side effects experienced with mRNA (Pfizer-BioNTech and Moderna) vaccinations in immunocompromised cancer patients compared with CDC VAERS database between December 15th, 2020, through July 31st, 2021.
Authors: Shivang Danak, Celine Fadel, Ania Rynarzewska, Drew Dalton, Louise Jones, Andrew Thomas Johnson
Journal: Journal of Clinical Oncology (2022)

e18782 Background: Immunotherapy is becoming a common therapy in cancer patients. Cancer patients on systemic therapy are a vulnerable population, making them highly susceptible to illness from any infection. The purpose of this study was to collect and analyze data reported by patients regarding the side effects of COVID-19 vaccines (Pfizer-BioNTech and Moderna) in cancer patients with solid tumors receiving immunotherapy. Due to the lack of studies and inclusion of cancer patients in the clinical trials for the vaccine, it is pivotal to investigate of the effects of the SARS-2-CoV vaccine on patients receiving immunotherapy to begin to bridge the current gap in knowledge. Methods: We performed a two-phased retrospective analysis of adult patients (age ≥18 years) who received either Moderna or Pfizer-BioNTech COVID-19 vaccinations and were currently on immunotherapy (December 15th, 2020, through July 31st, 2021). Phase 1 included a tertiary health system (n = 15,910) in Northeast Georgia. Phase 2 involved cross-tabulation with the VAERS CDC database to compare results at a national level (n = 374,667). The primary endpoints were severity of side effects, timing of side effects and the relationship between the vaccines. The method to evaluate outcome was the Pearson-Chi-Squared test. Results: Results showed that patients on immunotherapy were more likely to have at least one side effect in the tertiary health system (OR 6.727 [95% CI, 2.748 - 16.465] compared to least two side effects in the national dataset (X² = 7.032, p &lt; 0.05). This difference was driven by the Moderna vaccine recipients, demonstrating a higher likelihood of experiencing two or more side effects (X² = 6.159, p &lt; 0.05). Those receiving the Pfizer-BioNTech vaccine did not demonstrate statistically significant side effects. The most common reaction noted was weakness in both datasets, which was more likely to occur after the Moderna vaccine. Gender analysis showed no difference in side effects in those receiving immunotherapy. In terms of timing of side effects, patients on immunotherapy (M = 10.66, SD = 25.1) had a delayed side effect onset of 10 days vs. four days. (M = 4.72, SD = 15.5, p &lt; 0.05). Conclusions: Both local and national datasets demonstrate cancer patients receiving immunotherapy compared to those that were on immunotherapy, were more likely to experience mild vaccine side effects, specifically weakness being the most common. There was no statistically significant increase in more serious adverse reactions. Additionally, side effect onset was delayed in patients on immunotherapy. These findings provide a foundation for understanding mRNA vaccines in patients on immunotherapy, with future research needs involving larger sample sizes.